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A deep generative classifier employs Short Run Markov Chain Monte Carlo inference with Langevin dynamics and backpropagation through time. In contrast to a convolutional neural network (ConvNet) with analogous architecture, the Short Run classifier approaches the same classification accuracy and (1) may synthesize data, (2) may learn unsupervised from additional unannotated data, and (3) exhibits robustness to adversarial attacks, due to the stochasticity of the Langevin equation and the top-down architecture of the generator network. The ConvNet classifier lacks the ability to perform (1) or (2) and possesses no defense against adversarial attacks, a critical concern for any deployed machine learning system. Meanwhile, the Short Run classifier demonstrates the capacity to improve in both classification accuracy and the quality of data synthesis, given additional unannotated data.

A deep generative classifier employs Short Run Markov Chain Monte Carlo inference with Langevin dynamics and backpropagation through time. In contrast to a convolutional neural network (ConvNet) with analogous architecture, the Short Run classifier approaches the same classification accuracy and (1) may synthesize data, (2) may learn unsupervised from additional unannotated data, and (3) exhibits robustness to adversarial attacks, due to the stochasticity of the Langevin equation and the top-down architecture of the generator network. The ConvNet classifier lacks the ability to perform (1) or (2) and possesses no defense against adversarial attacks, a critical concern for any deployed machine learning system. Meanwhile, the Short Run classifier demonstrates the capacity to improve in both classification accuracy and the quality of data synthesis, given additional unannotated data.

Accumulation of misfolded, aggregating proteins concurrent with disease onset and progression is a hallmark of neurodegenerative proteinopathies. An important class of these are tauopathies, such as frontotemporal dementia (FTD) and Alzheimers disease (AD), associated with accumulation of aberrant forms of tau protein in the brain. Pathological tau undergoes abnormal post-translational modifications, misfolding, oligomerization and changes in solubility, cellular redistribution, and spreading. Development and testing of experimental therapeutics that target these pathological tau conformers requires use of cellular models that recapitulate neuronal endogenous, non-heterologous tau expression under genomic and physiological contexts relevant to disease. In this study, we employed FTD-patient induced pluripotent stem cells (iPSC)-derived neurons, expressing a tau variant or mutation, as primary models for driving a medicinal chemistry campaign around tau targeting degrader series. Our screening goal was to establish structure-activity relationships (SAR) for the different chemical series to identify the molecular composition that most efficiently led to tau degradation in human FTD ex vivo neurons. We describe the identification of the lead compound QC-01-175 and follow-up optimization strategies for this molecule. We present three final lead molecules with tau degradation activity in mutant neurons, which establishes potential disease relevance and will drive future studies on specificity and pharmacological properties.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to spread relentlessly, associated with a high frequency of respiratory failure and mortality. Children experience largely asymptomatic disease, with rare reports of multisystem inflammatory syndrome in children (MIS-C). Identifying immune mechanisms that result in these disparate clinical phenotypes in children could provide critical insights into coronavirus disease 2019 (COVID-19) pathogenesis. Using systems serology, in this study we observed in 25 children with acute mild COVID-19 a functional phagocyte and complement-activating IgG response to SARS-CoV-2, similar to the acute responses generated in adults with mild disease. Conversely, IgA and neutrophil responses were significantly expanded in adults with severe disease. Moreover, weeks after the resolution of SARS-CoV-2 infection, children who develop MIS-C maintained highly inflammatory monocyte-activating SARS-CoV-2 IgG antibodies, distinguishable from acute disease in children but with antibody levels similar to those in convalescent adults. Collectively, these data provide unique insights into the potential mechanisms of IgG and IgA that might underlie differential disease severity as well as unexpected complications in children infected with SARS-CoV-2., National Institute for Allergy and Infectious Diseases (Grant U19 AI135995), NIH (Grants 3R37AI080289-11S1, R01AI146785, U19AI42790-01, U19AI135995-02, U19AI42790-01, CIVIC75N93019C00052, U01CA260476), Gates Foundation (Grant OPP1146996)

This dissertation analyzes issues in monetary policy, global financial flows and financial stability. Chapters 2 and 3 are empirical and explore the effects of monetary policy on international debt flows to emerging markets and both debt and equity flows to Latin America. Chapter 4 is a theoretical agent based model of financial stability that examines systemic risk in financial networks with banks and non-financial transactors.

This dissertation analyzes issues in monetary policy, global financial flows and financial stability. Chapters 2 and 3 are empirical and explore the effects of monetary policy on international debt flows to emerging markets and both debt and equity flows to Latin America. Chapter 4 is a theoretical agent based model of financial stability that examines systemic risk in financial networks with banks and non-financial transactors.

Cyclin-dependent kinase 9 (CDK9), an important regulator of transcriptional elongation, is a promising target for cancer therapy, particularly for cancers driven by transcriptional dysregulation. We characterized NVP-2, a selective ATP-competitive CDK9 inhibitor, and THAL-SNS-032, a selective CDK9 degrader consisting of a CDK-binding SNS-032 ligand linked to a thalidomide derivative that binds the E3 ubiquitin ligase Cereblon (CRBN). To our surprise, THAL-SNS-032 induced rapid degradation of CDK9 without affecting the levels of other SNS-032 targets. Moreover, the transcriptional changes elicited by THAL-SNS-032 were more like those caused by NVP-2 than those induced by SNS-032. Notably, compound washout did not significantly reduce levels of THAL-SNS-032-induced apoptosis, suggesting that CDK9 degradation had prolonged cytotoxic effects compared with CDK9 inhibition. Thus, our findings suggest that thalidomide conjugation represents a promising strategy for converting multi-targeted inhibitors into selective degraders and reveal that kinase degradation can induce distinct pharmacological effects compared with inhibition.

In mammalian nucleotide excision repair, the DDB1-DDB2 complex recognizes UV-induced DNA photolesions and facilitates recruitment of the XPC complex. Upon binding to damaged DNA, the Cullin 4 ubiquitin ligase associated with DDB1-DDB2 is activated and ubiquitinates DDB2 and XPC. The structurally disordered N-terminal tail of DDB2 contains seven lysines identified as major sites for ubiquitination that target the protein for proteasomal degradation; however, the precise biological functions of these modifications remained unknown. By exogenous expression of mutant DDB2 proteins in normal human fibroblasts, here we show that the N-terminal tail of DDB2 is involved in regulation of cellular responses to UV. By striking contrast with behaviors of exogenous DDB2, the endogenous DDB2 protein was stabilized even after UV irradiation as a function of the XPC expression level. Furthermore, XPC competitively suppressed ubiquitination of DDB2 in vitro, and this effect was significantly promoted by centrin-2, which augments the DNA damage-recognition activity of XPC. Based on these findings, we propose that in cells exposed to UV, DDB2 is protected by XPC from ubiquitination and degradation in a stochastic manner; thus XPC allows DDB2 to initiate multiple rounds of repair events, thereby contributing to the persistence of cellular DNA repair capacity

Hydrostatic steering systems are used in construction and agricultural machines alike. Because of their high power density, hydraulic drives are qualified for the use in vehicles with high steering loads. Conventional hydrostatic steering systems are limited in terms of steering comfort and driver assistance. For realisation of appropriate steering functions, electro-hydraulic solutions are necessary. This paper provides an overview on existing implementations and introduces a novel steering system. The presented active steering system with independent meter-in and meter-out valves fills the gap between existing active steering systems and steer-by-wire solutions. An appropriate control and safety concept provides advanced steering functions for on-road usage without the fully redundant structure of steer-by-wire systems.

Measures of individualization and integration offer a great potential for further development and optimization in hydraulic drive technology. Advantages are seen especially for energy efficiency and functionality. These potentials motivate current research activities for displacement controlled systems and for valve controlled structures. For the latter, the focus lies on strategies of independent metering. Furthermore, expected challenges for the future are discussed.

Hydrostatic steering systems are used in construction and agricultural machines alike. Because of their high power density, hydraulic drives are qualified for the use in vehicles with high steering loads. Conventional hydrostatic steering systems are limited in terms of steering comfort and driver assistance. For realisation of appropriate steering functions, electro-hydraulic solutions are necessary. This paper provides an overview on existing implementations and introduces a novel steering system. The presented active steering system with independent meter-in and meter-out valves fills the gap between existing active steering systems and steer-by-wire solutions. An appropriate control and safety concept provides advanced steering functions for on-road usage without the fully redundant structure of steer-by-wire systems.

Measures of individualization and integration offer a great potential for further development and optimization in hydraulic drive technology. Advantages are seen especially for energy efficiency and functionality. These potentials motivate current research activities for displacement controlled systems and for valve controlled structures. For the latter, the focus lies on strategies of independent metering. Furthermore, expected challenges for the future are discussed.

Die Fragestellung dieser Arbeit lautete: „Wie wirkt sich eine möglich Belohnung auf die Lern- und Leistungsmotivation aus?“. Eine vernünftige Antwort auf diese Frage lässt sich aus dieser Arbeit nicht ableiten. Dies weil die erwähnte Fragestellung mittels eines Experiments ermittelt werden sollte. Die Resultate aus dem Experiment ergaben, dass diese Fragestellung nicht beantwortet werden konnte. Aus dem Experiment ergaben sich jedoch spannende Hypothesen, die mit Motivationstheorien verknüpft wurden. Anschliessend wurden die Hypothesen mit den ausgewerteten Daten aus dem Experiment und wiederum den Motivationstheorien verbunden. Es wurde unter anderem der Frage nachgegangen wie sich eine Belohnung auf die Aufgabenwahl der Schülerinnen und Schüler auswirkt. Da die Durchführung des Experiments mit der Zusammenführung der Theorien für den Ersteller der Arbeit rasch ein unzufriedenes Ergebnis aufzeigte, wurde in einem Kapitel beschrieben, was am experimentellen Versuch besser gemacht hätte werden sollen. Das Kapitel mit den Ableitungen für das Unterrichten und die schulische Praxis fiel eher kurz aus. Deshalb wurden noch persönliche Anmerkungen für das Unterrichten und die schulische Praxis gemacht.

Introduction: Current resuscitation guidelines emphasize a systems approach with a strong emphasis on quality cardiopulmonary resuscitation (CPR). Despite the American Heart Association (AHA) emphasis on quality CPR for over 10 years, resuscitation teams do not consistently meet recommended CPR standards. The objective is to assess the impact on chest compression depth of factors including bed height, step stool utilization, position of the rescuer’s arms and shoulders relative to the point of chest compression, and rescuer characteristics including height, weight, and gender. Methods: Fifty-six eligible subjects, including physician assistant students and first-year emergency medicine residents, were enrolled and randomized to intervention (bed lowered and step stool readily available) and control (bed raised and step stool accessible, but concealed) groups. We instructed all subjects to complete all interventions on a high-fidelity mannequin per AHA guidelines. Secondary end points included subject arm angle, height, weight group, and gender. Results: Using an intention to treat analysis, the mean compression depths for the intervention and control groups were not significantly different. Subjects positioning their arms at a 90-degree angle relative to the sagittal plane of the mannequin’s chest achieved a mean compression depth significantly greater than those compressing at an angle less than 90 degrees. There was a significant correlation between using a step stool and achieving the correct shoulder position. Subject height, weight group, and gender were all independently associated with compression depth. Conclusion: Rescuer arm position relative to the patient’s chest and step stool utilization during CPR are modifiable factors facilitating improved chest compression depth.

Introduction: Current resuscitation guidelines emphasize a systems approach with a strong emphasis on quality cardiopulmonary resuscitation (CPR). Despite the American Heart Association (AHA) emphasis on quality CPR for over 10 years, resuscitation teams do not consistently meet recommended CPR standards. The objective is to assess the impact on chest compression depth of factors including bed height, step stool utilization, position of the rescuer’s arms and shoulders relative to the point of chest compression, and rescuer characteristics including height, weight, and gender. Methods: Fifty-six eligible subjects, including physician assistant students and first-year emergency medicine residents, were enrolled and randomized to intervention (bed lowered and step stool readily available) and control (bed raised and step stool accessible, but concealed) groups. We instructed all subjects to complete all interventions on a high-fidelity mannequin per AHA guidelines. Secondary end points included subject arm angle, height, weight group, and gender. Results: Using an intention to treat analysis, the mean compression depths for the intervention and control groups were not significantly different. Subjects positioning their arms at a 90-degree angle relative to the sagittal plane of the mannequin’s chest achieved a mean compression depth significantly greater than those compressing at an angle less than 90 degrees. There was a significant correlation between using a step stool and achieving the correct shoulder position. Subject height, weight group, and gender were all independently associated with compression depth. Conclusion: Rescuer arm position relative to the patient’s chest and step stool utilization during CPR are modifiable factors facilitating improved chest compression depth.

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(DLPS) 5571095.0567.009, http://name.umdl.umich.edu/5571095.0567.009, http://quod.lib.umich.edu/t/text/accesspolicy.html, Where applicable, subject to copyright. Other restrictions on distribution may apply. Please go to http://www.umdl.umich.edu/ for more information.

The Department of Defense (DOD) is the single largest energy consumer in the nation. As the largest owner of federal data centers, with 772, the DOD has more than twice as many centers as any other agency. By consolidating some of its data centers, DOD could have a significant positive impact on energy savings for the federal government. DOD has instituted a number of policy directives, as have all federal agencies, that influence energy use in its data centers. Data centers are facilities buildings or parts of buildings used to store, manage, and disseminate electronic information for a computer network. They house servers, which are computers used to perform network-management functions such as data storage and processing, and communications equipment and devices to connect the servers with the network. Data centers usually draw their power from the electric grid, but they may also contain specialized power conversion and backup equipment to maintain reliable power. Power consumption varies greatly among data centers but is typically many times higher than for other kinds of buildings. Within the context of the FDCCI, DOD s efforts are intended to address concerns about rising energy demands and costs of data centers, associated increases in carbon emissions, expanding real-estate footprints of data centers, and rising real-estate costs. According to DOD, the Department plans to reduce the number of its data centers by about 30% by 2013, and the number of servers by 25%. DOD intends to use savings generated from consolidation to pay the consolidation costs. DOD also plans to use cloud computing as part of its savings effort., CRS Report for Congress

For more than a decade, various experts have expressed increasing concerns about cybersecurity, in light of the growing frequency, impact, and sophistication of attacks on information systems in the United States and abroad. Consensus has also been building that the current legislative framework for cybersecurity might need to be revised. The complex federal role in cybersecurity involves both securing federal systems and assisting in protecting nonfederal systems. Under current law, all federal agencies have cybersecurity responsibilities relating to their own systems, and many have sector-specific responsibilities for critical infrastructure. More than 50 statutes address various aspects of cybersecurity either directly or indirectly, but there is no overarching framework legislation in place. While revisions to most of those laws have been proposed over the past few years, no major cybersecurity legislation has been enacted since 2002., CRS Report for Congress

Even before the terrorist attacks of September 2001, concerns had been rising among security experts about the vulnerabilities to attack of computer systems and associated infrastructure. Yet, despite increasing attention from federal and state governments and international organizations, the defense against attacks on these systems has appeared to be generally fragmented and varying widely in effectiveness. Concerns have grown that what is needed is a national cybersecurity framework -- a coordinated, coherent set of public- and private-sector efforts required to ensure an acceptable level of cybersecurity for the nation. As commonly used, "cybersecurity" refers to three things: measures to protect information technology; the information it contains, processes, and transmits, and associated physical and virtual elements; the degree of protection resulting from application of those measures; and the associated field of professional endeavor. Virtually any element of cyberspace can be at risk, and the degree of interconnection of those elements can make it difficult to determine the extent of the cybersecurity framework that is needed. Identifying the major weaknesses in U.S. cybersecurity is an area of some controversy. However, some components appear to be sources of potentially significant risk because either major vulnerabilities have been identified or substantial impacts could result from a successful attack. There are several options for broadly addressing weaknesses in cybersecurity. They include adopting standards and certification, promulgating best practices and guidelines, using benchmarks and checklists, use of auditing, improving training and education, building security into enterprise architecture, using risk management, and using metrics., CRS Report for Congress.

The simultaneously hermaphroditic fish, Hypoplectrus nigricans, engages in a form of reciprocal spawning called “egg trading”, where one partner gives up eggs for fertilization in exchange for the opportunity to fertilize those of the partner. Since egg trading appears to be important in the evolutionary maintenance of hermaphroditism in H. nigricans, an attempt was made to determine if another species, Serranus tortugarum, behaved in a similar fashion. S. tortugarum do trade eggs, and the phenomenon seems to be widespread in simultaneously hermaphroditic serranids. However, the cues for spawning are much subtler than in H. nigricans and other simultaneously hermaphroditic serranids. This trait appears to be an evolutionary response to the occurrence of heavy sperm competition in the form of streaking.

The simultaneously hermaphroditic fish, Hypoplectrus nigricans, engages in a form of reciprocal spawning called “egg trading”, where one partner gives up eggs for fertilization in exchange for the opportunity to fertilize those of the partner. Since egg trading appears to be important in the evolutionary maintenance of hermaphroditism in H. nigricans, an attempt was made to determine if another species, Serranus tortugarum, behaved in a similar fashion. S. tortugarum do trade eggs, and the phenomenon seems to be widespread in simultaneously hermaphroditic serranids. However, the cues for spawning are much subtler than in H. nigricans and other simultaneously hermaphroditic serranids. This trait appears to be an evolutionary response to the occurrence of heavy sperm competition in the form of streaking.

In mammalian nucleotide excision repair, the DDB1-DDB2 complex recognizes UV-induced DNA photolesions and facilitates recruitment of the XPC complex. Upon binding to damaged DNA, the Cullin 4 ubiquitin ligase associated with DDB1-DDB2 is activated and ubiquitinates DDB2 and XPC. The structurally disordered N-terminal tail of DDB2 contains seven lysines identified as major sites for ubiquitination that target the protein for proteasomal degradation; however, the precise biological functions of these modifications remained unknown. By exogenous expression of mutant DDB2 proteins in normal human fibroblasts, here we show that the N-terminal tail of DDB2 is involved in regulation of cellular responses to UV. By striking contrast with behaviors of exogenous DDB2, the endogenous DDB2 protein was stabilized even after UV irradiation as a function of the XPC expression level. Furthermore, XPC competitively suppressed ubiquitination of DDB2 in vitro, and this effect was significantly promoted by centrin-2, which augments the DNA damage-recognition activity of XPC. Based on these findings, we propose that in cells exposed to UV, DDB2 is protected by XPC from ubiquitination and degradation in a stochastic manner; thus XPC allows DDB2 to initiate multiple rounds of repair events, thereby contributing to the persistence of cellular DNA repair capacity